Cardiac contractile dysfunction in insulin-resistant rats fed a high-fat diet is associated with elevated CD36-mediated fatty acid uptake and esterification

Abstract

Aims/hypothesis Changes in cardiac substrate utilisation leading to altered energy metabolism may underlie the development of diabetic cardiomyopathy. We studied cardiomyocyte substrate uptake and utilisation and the role of the fatty acid translocase CD36 in relation to in vivo cardiac function in rats fed a high-fat diet (HFD). Methods Rats were exposed to an HFD or a low-fat diet (LFD). In vivo cardiac function was monitored by echocardiography. Substrate uptake and utilisation were determined in isolated cardiomyocytes.Results Feeding an HFD for 8 weeks induced left ventricular dilation in the systolic phase and decreased fractional shortening and the ejection fraction. Insulin-stimulated glucose uptake and proline-rich Akt substrate 40 phosphorylation were 41% (p<0.001) and 45% (p<0.05) lower, respectively, in cardiomyocytes from rats on the HFD. However, long-chain fatty acid (LCFA) uptake was 1.4-fold increased (p<0.001) and LCFA esterification into triacylglycerols and phospholipids was increased 1.4-and 1.5-fold, respectively (both p<0.05), in cardiomyocytes from HFD compared with LFD hearts. In the presence of the CD36 inhibitor sulfo-N-succinimidyloleate, LCFA uptake and esterification were similar in LFD and HFD cardiomyocytes. In HFD hearts CD36 was relocated to the sarcolemma, and basal phosphorylation of a mediator of CD36-trafficking, i.e. protein kinase B (PKB/Akt), was increased. Diabetologia (2007) 50:1938-1948 DOI 10.1007 Electronic supplementary material The online version of this article (doi:10.1007/s00125-007-0735-8) contains supplementary material, which is available to authorised users. Conclusions/interpretation Feeding rats an HFD induced cardiac contractile dysfunction, which was accompanied by the relocation of CD36 to the sarcolemma, and elevated basal levels of phosphorylated PKB/Akt. The permanent presence of CD36 at the sarcolemma resulted in enhanced rates of LCFA uptake and myocardial triacylglycerol accumulation, and may contribute to the development of insulin resistance and diabetic cardiomyopathy.

Assessment of epicardial fat volume and myocardial triglyceride content in severely obese subjects: relationship to metabolic profile, cardiac function and visceral fat

“…Furthermore, it is suggested that inflammatory signals produced by EF, associated with low levels of adiponectin, may increase the membrane localization of CD36 in cardiomyocytes and consequently increase myocardial lipid uptake. 49 Cardiac adiposity and heart function in obesity B Gaborit et al EFV and MTGC are related to each other, but do not accumulate in a similar way. The molecular characteristics of EF are perhaps as important as EFV.…”

Rodent models of diabetic cardiomyopathy

“…The onset of cardiac dysfunction following Western diets is more rapid in Wistar rats, in which high-fat feeding for 7 weeks leads to myocardial steatosis, impaired contractile function and mitochondrial degeneration. Myocardial fatty acid uptake is increased in Wistar rats fed on a Western diet owing to increased sarcolemmal CD36 (Ouwens et al, 2005;Ouwens et al, 2007). Substrate oxidation and myocardial oxygen consumption have not yet been evaluated in this model.…”

Myocardial Insulin Resistance: An Overview of Its Causes, Effects, and Potential Therapy

“…High fat feeding induced insulin resistance in C57BL/6 mice also causes cardiac remodelling and systolic dysfunction [202]. The authors and other research groups have however also shown that rodent models of diet-induced obesity with insulin resistance have either normal [90,203,205,209,210] or compromised [110,203,204,211,212] cardiac mechanical function. It is currently not possible to conclusively attribute the cardiac dysfunction reported in these studies to myocardial insulin resistance since there are several studies that have reported normal cardiac function in animal models with insulin resistance [90,203,205,209,210].…”